Synthesis of idebenone; a synthetic analog of coenzyme Q

Article abstract of DOI:10.1081/SCC-100105319

Idebenone, a synthetic analog of coenzyme Q, was prepared from the tetramethoxytoluene 2. Two main transformations in this procedure are Friedel-Crafts acylation of 2 to 4 and CAN assisted oxidation of 7 to the quinone 8.

Full text of DOI:10.1081/SCC-100105319

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SYNTHESIS OF IDEBENONE; A SYNTHETIC ANALOG OF
COENZYME Q
Young-Sik Jung a , Bo-Young Joe a , Churl-Min Seong a & No-Sang Park a
a Bioorganic Division , Korea Research Institute of Chemical Technology , P.O. Box 107,
Yusong, Taejon, 305 606, Korea
Published online: 15 Aug 2006.
To cite this article: Young-Sik Jung , Bo-Young Joe , Churl-Min Seong & No-Sang Park (2001) SYNTHESIS OF IDEBENONE; A
SYNTHETIC ANALOG OF COENZYME Q, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:18, 2735-2741, DOI: 10.1081/SCC-100105319
To link to this article: http://dx.doi.org/10.1081/SCC-100105319
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SYNTHETIC COMMUNICATIONS, 31(18), 2735–2741 (2001)
SYNTHESIS OF IDEBENONE;
A SYNTHETIC ANALOG OF
COENZYME Q
Young-Sik Jung,* Bo-Young Joe, Churl-Min Seong,
and No-Sang Park*
Bioorganic Division, Korea Research Institute of
Chemical Technology, P.O. Box 107,
Yusong, Taejon 305 606, Korea
ABSTRACT
Idebenone, a synthetic analog of coenzyme Q, was prepared
from the tetramethoxytoluene 2. Two main transformations
in this procedure are Friedel–Crafts acylation of 2 to 4 and
CAN assisted oxidation of 7 to the quinone 8.
Idebenone1 (2,3-dimethoxy-5-methyl-6-(10-hydroxy)decyl-1,4-benzo-
quinone) is a synthetic analog of coenzyme Q2 which is a lipid-soluble
electron carrier that functions in a critical position in the mitochondria
electron transport chain. Although the precise mechanism of action of ide-
benone is unknown, preclinical studies suggest that idebenone may exert
cytoprotective properties by acting as a free radical scavenger.1 In addition,
it also appears to improve cerebral metabolism, correct neurotransmitter
defects, and enhance memory and learning. The study of structurally
*Corresponding author.
2735
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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JUNG ET AL.
varied derivatives for biological testing led us to investigate idebenone
synthesis. The first synthesis of idebenone was reported by the workers of
Takeda in many years ago,3 and efficient synthesis is still desirable.
In this report, we wish to describe the synthesis of idebenone starting
from readily available tetramethoxytoluene 2.4 The AlCl3 catalyzed acyla-
tion of 2 with acid chloride 35 in CH2Cl2 provided 4 (71%). Reduction of 4
with LiAlH4 followed by acetylation with acetic anhydride gave 5 (88%).
Selective removal of the acetyl group on benzylic position under Pd-cata-
lyzed hydrogenation condition was attempted. Even though many examples
for the reduction of acetyl group are appeared in literatures,6 no reaction
was occurred in our system. Thus this problem was solved by two consecu-
tive reactions, elimination using LiBr in DMF (49%)7 and then Pd-cata-
lyzed hydrogenation (99%), to provide 7. Oxidation of 7 with ceric
ammonium nitrite (CAN)8 in aqueous MeCN followed by hydrolysis with
Na2CO3 provided 1 (54%). In summary, we accomplished the synthesis of
idebenone from readily available tetramethoxytoluene 2. Two main trans-
formations in this procedure are Friedel–Crafts acylation of 2 to 4 and CAN
assisted oxidation of 7 to the quinone 8.
EXPERIMENTAL
All reactions were carried out under N2 atmosphere unless otherwise
noted. MeCN was distilled from CaH2 prior to use. Organic extracts or
filtrates were washed with brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo. Flash chromatography was performed with Merck-EM
1
Type 60 (230–400 mesh) silica gel (flash). H NMR spectra were measured
by Varian Gemini 200 MHz and Bruker AM-300 NMR spectrometers.
Chemical shifts are reported in ppm (d) relative to TMS as internal stan-
dard. Mass spectrometric data determined by use of the electron impact
(EIMS) method are reported as m/z (relative intensity). Elemental analyses
were performed with CE Instruments-ea 1110Automatic Elemental Analyzer.
Melting points were uncorrected.

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IDEBENONE
2737
Methyl10-(2,3,4,5-Tetramethoxy-6-methypl heny)l-10-
undecenoate (4)
To a mixture of AlCl3 (944 mg, 7.02 mmol) in CH2Cl2 (10mL) was
added acid chloride 3 (1.6 mL, 7.02 mmol) followed by 1,2,3,4-tetra-
methoxy-5-methylbenzene 2 (1.27 g, 5.4 mmol) in CH2Cl2 (10mL) at 0 ꢀC
and then the mixture was refluxed for 24 h. The reaction mixture was
quenched with cold water and extracted with CH2Cl2. The organic extracts
were dried over Na2SO4. Evaporation of solvents afforded a crude, which
was purified by flash chromatography (silica gel, hexane : EtOAc ¼ 4:1) to

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JUNG ET AL.
provide 4 (1.57 g, 71%). 1H NMR (200 MHz, CDCl3) d 1.28 (br s, 8H,
4CH2), 1.60–1.64 (m, 4H, 2CH2), 2.02 (s, 3H, ArCH3), 2.27 (t, J ¼ 7.4 Hz,
2H, CH2), 2.69 (t, J ¼ 7.3 Hz, 2H, CH2), 3.64 (s, 3H, CO2CH3), 3.76 (s, 3H,
ArOCH3), 3.77 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3);
13C NMR (75 MHz, CDCl3) 11.9, 23.4, 24.8, 29.0, 29.2, 34.0, 45.0, 51.4,
60.6, 61.0, 61.1, 61.8, 122.6, 131.9, 144.5, 145.7, 147.6, 148.1, 174.3, 207.1;
MS m/z (rel. intensity) 410(M þ, 15), 239 (100); HRMS (EI) calcd for
C22H34O7 410.23, found 410.23; Elemental analysis, calcd for C22H34O7:
C, 64.37; H, 8.35, found C, 65.13; H, 8.71.
10-Methylcarbonyloxy-1-(2,3,4,5-tetramethoxy-
6-methylphenyl)decylacetate (5)
To a mixture of LAH (550mg, 14.4 mmol) in THF (10mL) was added
a solution of 4 (740mg, 1.8 mmol) in THF (5 mL) at 0 ꢀC. After stirring at
0ꢀC for 1 h, the mixture was quenched with MeOH. Filtration followed
by evaporation of solvents afforded a crude, which was purified by flash
chromatography (silica gel, hexane : EtOAc ¼ 1:1) to provide 1-(2,3,4,5-tet-
ramethoxy-6-methylphenyl)-1,10-decenediol (639 mg, 92%). To a solution of
the diol (639 mg, 1.6 mmol)andDMAP (20mg, 0.16 mmol) in CH Cl2 (10mL)
2
was added acetic anhydride (0.4 mL, 4 mmol) and Et3N (1 mL, 7 mmol) at
0ꢀC. After being stirred at r.t. for 7 h, the mixture was diluted with CH2Cl2.
The resulting solution was washed with water and the organic fraction was
dried over Na2SO4. Evaporation of solvent afforded a crude, which was
purified by flash chromatography (silica gel, hexane : EtOAc ¼ 2:1) provided
1
5 (721 mg, 96%). H NMR (200 MHz, CDCl3) d 1.27 (br s, 12H, 6CH2),
1.57–1.80(m, 4H, 2CH ), 2.05 (s, 3H, OCOCH3), 2.06 (s, 3H, OCOCH3),
2.30(s, 3H, ArCH ), 3.77 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.89 (s, 3H,
2
3
OCH3), 3.91 (s, 3H, OCH3), 4.04 (t, J ¼ 6.7 Hz, 2H, CH2), 6.20(t,
J ¼ 6.4 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) 12.0, 20.9, 21.2, 25.8,
26.0, 28.5, 29.1, 29.2, 29.3, 29.3, 34.0, 60.5, 60.9, 60.9, 61.1, 64.6, 71.4,
125.4, 127.3, 144.7, 146.4, 148.2, 170.5, 171.2; MS m/z (rel. intensity) 468
(Mþ, 91), 408 (100), 377 (26), 266 (29), 241 (73), 225 (47), 105 (26); HRMS
(EI) calcd for C25H40O8 468.27, found 468.27; Elemental analysis, calcd for
C25H40O8: C, 64.08; H, 8.60, found C, 65.28; H, 9.07.
10-(2,3,4,5-Tetramethoxy-6-methylphenyl)-9-decenylacetate (6)
A mixture of the acetate 5 (25 mg, 0.05 mmol) and LiBr (108 mg,
1.25 mmol) in DMF (0.5 mL) was heated at 120ꢀC for 24 h. Water (5 mL)

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IDEBENONE
2739
was added and the mixture was extracted with diethyl ether (5 mLꢁ3).
The organic extracts were dried over Na2SO4. Evaporation of solvents
afforded a crude, which was purified by flash chromatography (silica gel,
hexane : EtOAc ¼ 4:1) to provide 6 (10mg, 49%). 1H NMR (200 MHz,
CDCl3) d 1.33 (br s, 12H, 6CH2), 1.44–1.62 (m, 4H, 2CH2), 2.04 (s, 3H,
OCOCH3), 2.19 (s, 3H, ArCH3 ), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
3.90(s, 3H, OCH ), 3.92 (s, 3H, OCH3), 4.05 (t, J ¼ 6.7 Hz, 2H, AcOCH2),
3
5.92–6.03 (m, 1H, ArCH ¼ CH), 6.24 (d, J ¼ 16.0Hz, 1H, ArC H ¼ CH);
13C NMR (75 MHz, CDCl3) 12.9, 20.9, 25.9, 28.6, 29.0, 29.2, 29.4, 33.8,
60.4, 60.6, 61.1, 61.2, 64.6, 123.1, 124.8, 127.2, 136.4, 144.8, 145.4, 146.6,
147.9, 171.2; MS m/z (rel. intensity) 408 (Mþ, 100), 377 (7), 334 (4); HRMS
(EI) calcd for C23H36O6 408.25, found 408.25; Elemental analysis, calcd for
C23H36O6: C, 67.62; H, 8.88, found C, 67.39; H, 9.02.
10-(2,3,4,5-Tetramethoxy-6-methylphenyl)decylacetate (7)
A mixture of the olefin 6 (181 mg, 0.44 mmol) and 10% Pd/C (15 mg)
in MeOH (5 mL) was stirred under H2 atmosphere using a balloon at r.t. for
1 h. The mixture was passed a celite pad and the filtrate was concentrated
1
in vacuo to provide 7 (180mg, 99%). H NMR (300 MHz, CDCl3) d 1.32 (br
s, 12H, 6CH2), 1.50–1.56 (m, 4H, 2CH2), 2.05 (s, 3H, OCOCH3), 2.21 (s,
3H, ArCH3), 2.52 (t, J ¼ 7.8 Hz, 2H, ArCH2), 3.71 (s, 3H, OCH3), 3.76 (s,
3H, OCH3), 3.89 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.03 (t, J ¼ 6.7 Hz, 2H,
AcOCH2); 13C NMR (75 MHz, CDCl3) 11.5, 21.0, 25.9, 26.9, 28.6, 29.2,
29.4, 29.5, 30.1, 30.3, 60.6, 60.9, 61.0, 61.1, 64.6, 124.8, 130.3, 144.5,
144.7, 147.6, 147.7, 171.2; MS m/z (rel. intensity) 410(M þ, 100), 336 (10),
225 (60); HRMS (EI) calcd for C23H38O6 410.27, found 410.27.
10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-
cyclohexadienyl)decylacetate (8)
To a solution of 7 (180mg, 0.44 mmol) in MeCN (2 mL) was added a
solution of CAN (554 mg, 1 mmol) in H2O (1 mL) at 0ꢀC. After the mixture
was stirred for 15 min, water was added to the mixture, which was extracted
with EtOAc. The organic extract was dried over Na2SO4. Evaporation of
solvents afforded a crude, which was purified by flash chromatography (silica
gel, hexane : EtOAc ¼ 4:1) to provide 8 (148 mg, 88%). 1H NMR (200 MHz,
CDCl3) d 1.28 (br s, 12H, 6CH2), 1.58–1.60(m, 4H, 2CH ), 2.01 (s, 3H,
2
OCOCH3), 2.04 (s, 3H, ArCH3), 2.44 (br s, 2H, ArCH2), 3.99 (s, 3H,
2OCH3), 4.05 (t, J ¼ 6.6 Hz, 2H, AcOCH2); 13C NMR (75 MHz, CDCl3)

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JUNG ET AL.
11.9, 21.0, 25.9, 26.3, 28.5, 28.7, 29.2, 29.3, 29.4, 29.8, 61.1, 61.8, 64.6, 72.3,
138.6, 143.0, 144.3, 171.2, 184.1, 184.7; MS m/z (rel. intensity) 380(M þ, 32),
338 (57), 196 (100), 184 (46); HRMS (EI) calcd for C21H32O6 380.22, found
380.22; Elemental analysis, calcd for C21H32O6: C, 66.29; H, 8.48; O, 25.23,
found C, 65.17; H, 8.74; O, 24.18.
2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methylbenzo-1,4-quinone (1)
To a solution of the quinone 8 (98 mg, 0.25 mmol) in MeOH/H2O
(1.6 mL/0.4 mL) was added Na2CO3 (6 mg, 0.052 mmol) at 0ꢀC and the
mixture was stirred at 0ꢀC for 36 h. Water was added and the mixture
was extracted with EtOAc. The organic extract was dried over Na2SO4.
Evaporation of solvents afforded a crude, which was purified by recrystalli-
1
zation (EtOAc/hexane) to provide the idebenone 1 (52 mg, 61%). H NMR
(300 MHz, CDCl3) d 1.28–1.62 (m, 16H, 8CH2), 2.04 (s, 3H, ArCH3), 2.44
(br s, 2H, ArCH2), 3.63 (t, J ¼ 6.7 Hz, 2H, AcOCH2), 3.98 (s, 6H, 2OCH3);
13C NMR (75 MHz, CDCl3) 11.9, 25.7, 26.3, 28.6, 29.3, 29.3, 29.5, 29.8,
32.8, 61.1, 63.1, 138.6, 143.1, 144.2, 184.1, 184.7; MS m/z (rel. intensity)
338 (Mþ, 81), 308 (21), 197 (100), 183 (47); HRMS (EI) calcd for C19H30O5
338.21, found 338.21; Elemental analysis, calcd for C19H30O5: C, 67.43; H,
8.93; O, 23.64, found C, 67.06; H, 9.15; O, 21.44; m.p. 50–53ꢀC.
ACKNOWLEDGMENTS
Financial support of this work by the Ministry of Science and
Technology in Korea is gratefully acknowledged.
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Received in Japan July 31, 2000

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